A critical role for Phocaeicola vulgatus in negatively impacting metformin response in diabetes.
10.1016/j.apsb.2025.02.008
- Author:
Manyun CHEN
1
;
Yilei PENG
1
;
Yuhui HU
1
;
Zhiqiang KANG
2
;
Ting CHEN
3
;
Yulong ZHANG
1
;
Xiaoping CHEN
1
;
Qing LI
1
;
Zuyi YUAN
4
;
Yue WU
4
;
Heng XU
5
;
Gan ZHOU
1
;
Tao LIU
6
;
Honghao ZHOU
1
;
Chunsu YUAN
7
;
Weihua HUANG
1
;
Wei ZHANG
1
Author Information
1. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China.
2. Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou 450007, China.
3. Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha 410208, China.
4. Department of Cardiology, Cardiovascular Research Center, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
5. Department of Laboratory Medicine, National Key Laboratory of Biotherapy/ Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
6. Shenzhen Center for Chronic Disease Control and Prevention, Shenzhen 518020, China.
7. Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL 60637, USA.
- Publication Type:Journal Article
- Keywords:
Ceramide;
Deconjugated bile acids;
Farnesoid X receptor;
Gut microbiota;
Metformin resistance;
Mitochondrial dysfunction;
Oxidative phosphorylation;
Thermogenesis
- From:
Acta Pharmaceutica Sinica B
2025;15(5):2511-2528
- CountryChina
- Language:English
-
Abstract:
Metformin has been demonstrated to attenuate hyperglycaemia by modulating the gut microbiota. However, the mechanisms through which the microbiome mediates metformin monotherapy failure (MMF) are unclear. Herein, in a prospective clinical cohort study of newly diagnosed type 2 diabetes mellitus (T2DM) patients treated with metformin monotherapy, metagenomic sequencing of faecal samples revealed that Phocaeicola vulgatus abundance was approximately 12 times higher in nonresponders than in responders. P. vulgatus rapidly hydrolysed taurine-conjugated bile acids, leading to ceramide accumulation and reversing the improvements in glucose intolerance conferred by metformin in high-fat diet-fed mice. Interestingly, C22:0 ceramide bound to mitochondrial fission factor to induce mitochondrial fragmentation and impair hepatic oxidative phosphorylation in P. vulgatus-colonized hyperglycaemic mice, which could be exacerbated by metformin. This work suggests that metformin may be unsuitable for P. vulgatus-rich T2DM patients and that clinicians should be aware of metformin toxicity to mitochondria. Suppressing P. vulgatus growth with cefaclor or improving mitochondrial function using adenosylcobalamin may represent simple, safe, effective therapeutic strategies for addressing MMF.
